Medical Science Symposia Series – serie

This volume contains the Proceedings of the invited lectures of the Second International Sym­ posium on SEROTONIN from Cell Biology to Pharmacology and Therapeutics held in Houston, Texas September 15-18, 1992. The meeting was held under the co-sponsorship of the Serotonin Club, the Giovanni Lorenzini Medical Foundation, and the Fondazione Giovanni Lorenzini. This volume discusses the major exploration in knowledge that has occurred recently of the complex role that 5- hydroxytryptamine (serotonin) plays in health and disease. In par­ ticular, these Proceedings highlight major breakthroughs in molecular biology and classification of receptor subtypes that are responsible for the many actions of the monoamine. The ever­ increasing importance of serotonin in central regulation, whether autonomic or behavioral is represented by a large number of chapters prepared by world experts. Additionally, the role of serotonin in peripheral organs is also discussed. Hence, this volume provides the reader with a unique, up-to-date review of this exciting and novel area of science. These Proceedings obviously are of great interest, not only to the researchers directly engaged in the quest for the understanding and unraveling of the actions of the interactions with serotonin as a major neurohumoral mediator, but also to all scholars and clinicians who wish to acquire a better understanding of the functioning of the brain and of peripheral organs. Since this volume was constructed as a compilation of invited lectures, the scientific content and the opinions expressed in the chapters are the sole responsibility of the authors.

The reasons why an immune system should attack itself are far from clear. The input of the biotechnogical revolution has enabled us to readdress many of the fundamental questions raised by clinical and serological associations with autoimmune disease. The ability to dissect the immune response to those infectious agents that are associated with autoimmune features, in addition to the ability to clone and sequence immune response genes, has given us a much better understanding of the complexity of "autoimmunity". This volume, a collection of papers from the BIOTECH '93 symposium with the same title, is a clear and informative summary of its theme.

As the number of drugs acting on calcium and potassium channels grows, there is a need for a continuous reappraisal of the cellular machinery controlling them. The present volume provides an update on the basic knowledge, the molecular targets of the two channels, and the importance the drugs that bind them have as pharmacological tools and therapeutic agents. This work was presented at the 6th International Symposium on PHARMACOLOGICAL CONTROL OF CALCIUM AND POTASSIUM HOMEOSTASIS: BIOLOGICAL, THERAPEUTICAL, AND CLINICAL ASPECTS, in Florence (Italy) on October 4-6, 1994. Because of the recent advances in the field, discussions on potassium channels were included for the first time. At least six classes of voltage-dependent calcium channels have been defined based on their physiological and pharmacological properties. Among them, L-type channels, mediating long lasting currents, are better characterized. Calcium homeostasis within the cell is not only regulated by calcium channels; intracellular calcium stores, in particular a pool contained in the lumen of specialized areas of the endoplasmic reticulum, are rapidly exchanged with the cytoplasm and playa key role in the control of calcium homeostasis. This area, however, has not yet been exploited from a therapeutic point of view. Potassium channels are present in virtually every cell type, excitable and nonexcitable, and are distinguished by structural, biophysical, and pharmacological criteria. Different classes including voltage-gated, ligand-gated, AP-sensitive, and G-protein coupled among others, have been defined by their primary regulatory and gating mechanisms.

List of Contributors xviii An Aging Humankind: New Realities E. Dicgalusy Does Menopause Increase the Risk of Coronary Heart Disease? M.V. Huisrnan Chronic Low-Grade Metabolic Acidosis in Normal Adult Humans: Pathophysiology and Consequences L. Frassetto, R.C. Morris, Jr., K. Todd, and A. Sebastian The Menopause, Sex Hormones, and Rheumatic Disease G. Hall Novel Mechanisms of Estrogen Action J.-A. Gustafsson The Action of Ovarian Steroid Hormones on Tissues and Organs M.J. Legato Nongenomic Mechanisms of Sex Hormones J.H.H. Thijssen Action of Specific Estrogens on Vascular Cells C.S. Wingrove and J.C. Stevenson Direct Actions of Estrogen on Vascular Cells Ameliorates Response to hjury D. W. Losordo ix Newer Progestogens G. Samsioe IV. 11. Cardiovascular Disease: Risk Factors Related to Thrombosis G. de Gaetano, M.B. Donati, and L. Iacoviello Estrogen Effect upon Coronary Vasculature G.M.C. Rosano, F. Leonardo, and G. Panina Estrogen and Endothelial Function A. Virdis, L. Ghiadoni, I. Sudano, S. Pinto, S. Taddei, and A. Salvetti Action of Specific Estrogens on the Coronary Artery: Effects on Lipoproteins, Coagulation, and Fibrinolysis J.M.Sullivan Coronary Heart Disease in Women: Status 1998 N. K. Wenger Introduction to Osteoporosis C. Christiansen Genetics of Osteoporosis L. Masi, L. Gennari, A. Falchetti, and M.L. Brandi The Clinical Management of Osteoporosis S.E. Papapou los VI.

The 11th international Conference on ADVANCES IN PROSTAGLANDIN AND LEUKOTRIENE RESEARCH: BASICSCIENCEANDNEWCLlNICALApPLlCA TIONS was held, as in the past, in Florence, Italy, on June 4-8, 2000. A selection of lectures presented at the meeting is included in this volume, which continues the tradition of covering both basic and clinical aspects of prostaglandin and leukotriene research. At this meeting particular emphasis was given to the lipid mediator circuits of lipoxin and leukotrienes and to the expression ofthe COX2 gene. The plenary lectures by C.N. Serhan (Boston, Massachusetts, U.S.A.) and H.R. Herschman (Los Angeles, California, U.S.A.) were devoted to these areas, while S. Narumiya (Kyoto, Japan) and J.M. Drazen (Boston, Massachusetts, U.S.A.) presented the latest advances in the fields ofprostanoid receptors and the genetics of asthma. Specific sessions focused on vascular physiopathology, cell differentiation and cancer, and the cardiovascular system. Lipoxygenases were discussed in detail at the molecular and cellular levels and attention was given to signal transduction pathways for leukotrienes and prostanoids. K.F. Austen (Boston, Massachusetts, U.S.A.) and T.Izumi (Tokyo, Japan) clarified the role and regulation ofLTC synthase ofleukotriene biosynthesis. Other important sessions 4 described regulation and control of nitric oxide, cannabimimetic eicosanoids, and the roles of eicosanoids in neuroscience. Applied clinical sessions devoted to the respiratory system and inflammation, including cyclooxygenase pathways, concluded the meeting.

The 4th International Symposium on Women's Health and Menopause, organized by the Giovanni Lorenzini Medical Foundation (Milan, Italy and Houston, Texas) focused on the new strategies to improve the quality of life of post-menopausal women.

Peroxisome proliferator activated receptors (PPARs) attract great attention in light of the wide spectrum of genes of biological and medical relevance identified as under their control. As a consequence, our knowledge of the role of these receptors in physiology and pathology continues to grow at a fast pace and PPARs have become an interesting target for the treatment of many pathological conditions, including diabetes and atherosclerosis. This volume provides an authoritative view of the clinical and scientific developments within this evolving area of study.

The 4th International Symposium on Women's Health and Menopause, organized by the Giovanni Lorenzini Medical Foundation (Milan, Italy and Houston, Texas) focused on the new strategies to improve the quality of life of post-menopausal women. This volume illustrates the findings of this conference and includes information on the age-related degenerative processes occurring after menopause including cardiovascular disease, cancer, fractures and dementia.

Peroxisome Proliferator Activated Receptors (PPARs) attract great attention in light of the wide spectrum of genes of biological and medical relevance identified as under their control.

The 11th international Conference on ADVANCES IN PROSTAGLANDIN AND LEUKOTRIENE RESEARCH: BASICSCIENCEANDNEWCLlNICALApPLlCA TIONS was held, as in the past, in Florence, Italy, on June 4-8, 2000. A selection of lectures presented at the meeting is included in this volume, which continues the tradition of covering both basic and clinical aspects of prostaglandin and leukotriene research. At this meeting particular emphasis was given to the lipid mediator circuits of lipoxin and leukotrienes and to the expression ofthe COX2 gene. The plenary lectures by C.N. Serhan (Boston, Massachusetts, U.S.A.) and H.R. Herschman (Los Angeles, California, U.S.A.) were devoted to these areas, while S. Narumiya (Kyoto, Japan) and J.M. Drazen (Boston, Massachusetts, U.S.A.) presented the latest advances in the fields ofprostanoid receptors and the genetics of asthma. Specific sessions focused on vascular physiopathology, cell differentiation and cancer, and the cardiovascular system. Lipoxygenases were discussed in detail at the molecular and cellular levels and attention was given to signal transduction pathways for leukotrienes and prostanoids. K.F. Austen (Boston, Massachusetts, U.S.A.) and T.Izumi (Tokyo, Japan) clarified the role and regulation ofLTC synthase ofleukotriene biosynthesis. Other important sessions 4 described regulation and control of nitric oxide, cannabimimetic eicosanoids, and the roles of eicosanoids in neuroscience. Applied clinical sessions devoted to the respiratory system and inflammation, including cyclooxygenase pathways, concluded the meeting.

This book includes the most significant contributions of the 3rd International Symposium on MULTIPLE RISK FACTORS IN CARDIOVASCULAR DISEASE held in Florence, Italy, July 6-9, 1994. The meeting focused on the risk factors for cardiovascular disease and their interactions. The need for this symposium is based on the epidemiological evidence that individuals from industrialized countries often possess two or more risk factors which synergistically increase the global risk profile. This has become more evident in recent years with the increase in life expectancy of the general population. The evidence that in high risk patients, a combination of risk factors often is detected, is highlighted in these Proceedings. Many recent epidemiological data identifYing the intrinsic and environmental factors contributing to the development of atherosclerosis are discussed. These results, in parallel with basic and clinical research, underline how atherosclerosis is a complex and multifactorial process involving the influences of lipids, including lipoprotein subfractions, blood pressure, rheologic forces, carbohydrate tolerance, and thrombogenic factors. Furthermore, the risk associated with anyone of these risk factors varies widely depending on level of the associated atherogenic risk factors.

As the number of drugs acting on calcium and potassium channels grows, there is a need for a continuous reappraisal of the cellular machinery controlling them. The present volume provides an update on the basic knowledge, the molecular targets of the two channels, and the importance the drugs that bind them have as pharmacological tools and therapeutic agents. This work was presented at the 6th International Symposium on PHARMACOLOGICAL CONTROL OF CALCIUM AND POTASSIUM HOMEOSTASIS: BIOLOGICAL, THERAPEUTICAL, AND CLINICAL ASPECTS, in Florence (Italy) on October 4-6, 1994. Because of the recent advances in the field, discussions on potassium channels were included for the first time. At least six classes of voltage-dependent calcium channels have been defined based on their physiological and pharmacological properties. Among them, L-type channels, mediating long lasting currents, are better characterized. Calcium homeostasis within the cell is not only regulated by calcium channels; intracellular calcium stores, in particular a pool contained in the lumen of specialized areas of the endoplasmic reticulum, are rapidly exchanged with the cytoplasm and playa key role in the control of calcium homeostasis. This area, however, has not yet been exploited from a therapeutic point of view. Potassium channels are present in virtually every cell type, excitable and nonexcitable, and are distinguished by structural, biophysical, and pharmacological criteria. Different classes including voltage-gated, ligand-gated, AP-sensitive, and G-protein coupled among others, have been defined by their primary regulatory and gating mechanisms.

Few topics in women's medicine today are as fraught with confusion and controversy as the question of appropriate treatment for menopausal symptoms and the prevention of negative long term health outcomes common to post-menopausal women. Cardiovascular disease (CVD), osteoporosis, and cancer -- the most common causes of death, disability and impaired quality of life for women -- can potentially be prevented or forestalled by dietary, behavioral, and drug interventions. A better understanding of the natural history of the menopause is critical to providing better care. If women and their physicians have a better understanding of predictors of risk, they could make more informed decisions about interventions related to menopausal symptoms, CVD, osteoporosis and gynecologic and breast cancer. Few other recently introduced medical interventions have as great a potential of affecting morbidity and mortality as does hormone replacement therapy (HRT). HRT has produced effect on health risk: some are reduced, some are raised, and some uncertain, and these data are interpreted differently by various scientific, medical and consumer groups.

The term "autoimmunity" has been used to categorize a number of different diseases of unknown etiology. The term as applied to many of these diseases would probably be interpreted best as "autoreactivity," as the clinical phenotypes are often characterized by an inflammatory-like accumulation of activated cells of the immune system at sites of obvious damage of normal cells and/or tissue. The reasons as to why an immune system should attack itself are far from clear, although the association with specific infectious diseases in genetically susceptible people remains perhaps our best lead. The input of the biotechnological revolution has enabled us to attempt to readdress many of the fundamental questions raised by clinical and serological associations with autoimmune disease. The ability to dissect the immune response to these infectious agents which are associated with autoimmune features (as well as the facility to identify new agents, e. g. HIV), in addition to the ability to clone and sequence immune response genes, has enabled a much better understanding, at least of the complexity of "autoimmunity" to be gleaned. This volume contains the chapters that summarize the plenary presentations given at The Impact of Biotechnology on AUTOIMMUNI1Y meeting in Florence, Italy in June 1993. They cover all aspects from pathogenesis to treatment. The association with infectious diseases and autoimmunity is comprehensively covered by David Isenberg who reviews major issues, such as the association of autoantibodies appearing after infectious disease and antibacterial antibodies associated with autoimmune disease.

A great deal of experimental, clinical and epidemiological data have been gathered to confirm the strict and causal correlation between plasma lipoproteins and coronary heart disease. However, as usually happens in research, many more interesting issues are being studied, opening new fields of research for the future. These new advances, together with the combined efforts of cell biologists and lipoprotein chemists, have set the pace for an exciting period of research and clinical applications of diets and drugs affecting plasma and cell lipids. This volume, which includes the work of many of the leading world labortories, represents an authoritative and up-to-date appraisal of the status of the art and a stimulus to future research at the laboratory and clinical level in a fascinating area of clinical and preventive medicine.

Although the importance of calcium (Ca2+) in the maintenance of cardiac contractility was recognized as early as 1880, the critical role of the ion in the contractile process in skeletal, cardiac, and smooth muscle has only been established within the last three decades.As the complexity of the pharmacological actions of the Ca2+ channel inhibitors grows, there is a continued need to further clarify the inhibitors, both chemically and functionally.This volume provides an update of the field based on the work presented at the 5th International Symposium on Calcium Antagonists: Pharmacology and Clinical Research. It reviews the current state of the growing area of molecular biology of Ca2+ channels. In the cardiovascular area, in addition to the well-established clinical uses of Ca2+ channel inhibitors, exciting new work pointing to an application in atherosclerosis is described. The book also includes important uses of Ca2+ antagonists in novel areas of interest such as the gastrointestinal tract, renal protection and multi-drug resistance.

This volume contains the Proceedings of the invited lectures of the Second International Sym­ posium on SEROTONIN from Cell Biology to Pharmacology and Therapeutics held in Houston, Texas September 15-18, 1992. The meeting was held under the co-sponsorship of the Serotonin Club, the Giovanni Lorenzini Medical Foundation, and the Fondazione Giovanni Lorenzini. This volume discusses the major exploration in knowledge that has occurred recently of the complex role that 5- hydroxytryptamine (serotonin) plays in health and disease. In par­ ticular, these Proceedings highlight major breakthroughs in molecular biology and classification of receptor subtypes that are responsible for the many actions of the monoamine. The ever­ increasing importance of serotonin in central regulation, whether autonomic or behavioral is represented by a large number of chapters prepared by world experts. Additionally, the role of serotonin in peripheral organs is also discussed. Hence, this volume provides the reader with a unique, up-to-date review of this exciting and novel area of science. These Proceedings obviously are of great interest, not only to the researchers directly engaged in the quest for the understanding and unraveling of the actions of the interactions with serotonin as a major neurohumoral mediator, but also to all scholars and clinicians who wish to acquire a better understanding of the functioning of the brain and of peripheral organs. Since this volume was constructed as a compilation of invited lectures, the scientific content and the opinions expressed in the chapters are the sole responsibility of the authors.

This book includes the most significant contributions of the First International Symposium on "Multiple risk factors in cardiovascular disease", chaired by Professors A. V. Chobanian (Boston), A. M. Gotto Jr. (Houston), c. Lenfant (Bethesda), R. Paoletti and A. Zanchetti (Milan), held in Washington DC, 10-12 December 1990, which focused on the risk factors for cardiovascular disease and their interactions. The need for this symposium is based on the epidemiological evidence that individuals from industrialized countries often possess two or more risk factors which synergically increase the global risk profile. The evidence that isolated vascular risk factors are not commonly found in high risk patients but more often a combination of risk factors are detected, is highlighted. Many recent epidemiological data identifying the intrinsic and environ­ mental factors contributing to the development of atherosclerosis are discussed. These results, in parallel to basic and clinical research, underline how atherosclerosis is a complex and multifac­ torial process involving the influences of lipid deposition, blood pressure, rheologic forces, carbohydrate tolerance, and thrombogenic factors (fibrinogen and platelets). Atherosclerosis is markedly accelerated by other risk factors, more so in the presence of concomitant hypercholes­ terolemia, hypertension, diabetes, upper body obesity. Furthermore, the risk associated with anyone of these risk factors varies widely depending on level of the associated atherogenic risk factors.

In Drugs and the Liver: High Risk patients and Transplantation, leading physicians, hepatologists, pharmacologists, pathologists and transplant surgeons discuss the most recent advances in the field of liver disease and their treatment. Attention is focused on epidemiology, the diagnosis of disease (clinical chemistry, histopathology, medical imaging analysis), prognosis, prediction, and clinical management. Pathogenesis of diseases such as liver cirrhosis following viral disease or alcohol abuse are discussed at length, and special attention is dedicated to high risk patients (children, fulminant hepatitis). The other major topics include terminal liver failure, for which transplantation is now routine. The latter is discussed in depth, starting from the organ donor management, organ evaluation and preservation, new surgical techniques, post-transplant patient follow-up including side effects of immunosuppression, and reports of the latest drugs used to prevent rejection.

This volume, based on the International Congress Creatine: From Basic Science to Clinical Application, held in Milan on June 4, 1999, outlines the physiological role of creatine in the human body as well as its possible role in different pathological conditions. Creatine is already used as a dietary supplement to augment muscle performance in healthy individuals and inpatients with immobilizing diseases, such as complex fractures. There is also an increasing interest in its administration in a growing number of clinical conditions. A specific deficit of endogenous synthesis of creatine which responds to high dosage exogenous supplementation has been described. In cardiac failure and in chronic obstructive pulmonary disease, creatine improves the contractility of the muscular system. Promising effects of this substance have also been described in animal models of neurodegenerative disorders, such as amyotrophic lateral sclerosis, and in some mitochondrial cytopathies. This volume is of obvious interest to basic scientists working on the physiology of creatine and to clinicians interested in its medical indications.

The effects of alcohol consumption on human health have fuelled a vigorous scientific debate in recent years. This volume, based on the scientific sessions of the International Meeting on MODERATE ALCOHOL CONSUMPTION AND CARDIOVASCULAR DISEASE, held in Venice October 30-31, 1999, is intended to offer an up-to-date view of the most recent information on this complex topic. While comprehension ofthe damages associated with alcohol abuse has improved, an increasing number of epidemiological studies performed in different countries of the world, have shown that individuals consuming moderate amounts of alcohol (l 0-30 g/day, approximately equivalent to not more than two drinks per day in men and one drink per day in women) are less affected by acute coronary events than total abstainers. The apparent protection is evident (the rate of coronary events in most studies is reduced by about 30%) and has been observed and documented among various population groups (men, women, several racial groups, middle-aged and older individuals). Protection is seen in patients with no known history of coronary heart disease, as well as in those with coronary heart disease, diabetes, etc. Recent data suggest that the protection induced by a moderate alcohol use extends to the risk of ischemic strokes and of ischemic damage to the lower limbs. Since adverse alcohol effects are less frequent at these low daily intakes, total mortality is also favourably affected in moderate alcohol consumers as compared to abstainers.

This volume is a collection of the most significant contributions to the 4th International Symposium on MULTIPLE RISK FACTORS IN CARDIOVASCULAR DISEASE: STRATEGIES OF PREVENTION OF CORONARY HEART DISEASE, CARDIAC F AlLURE, AND STROKE held in Washington, D. C. in April 1997. The meeting focused on the risk factors for cardiovascular disease and their interactions. The need for this symposium is based on the epidemiological, clinical, and biological evidence that individuals from industrialized countries often possess two or more risk factors which synergistically increase the global risk profile. This has become more evident in recent years with the increase in life expectancy of populations in the industrialized countries. The evidence that a combination of risk factors confers a very high risk of developing cardiovascular diseases, is of pivotal interest in the process of detection of patients who will benefit the most from pharmacological treatment. Many recent epidemiological data identifying the intrinsic and environmental factors contributing to the development of atherosclerosis are discussed. These results, in parallel with basic and clinical research, underline atherosclerosis as a complex and multifactorial process involving the influences of lipids, including lipoprotein subfractions, blood pressure rheologic forces, carbohydrate tolerance, and thrombogenic factors, including fibrinogen, tissue factor, PAl-I, and homocysteine. Furthennore, the risk associated with anyone of these risk factors varies widely depending on the level of the associated atherogenic risk factors. Hyper­ cholesterolemia and hypertriglyceridemia, for instance, are more common than would be expected by chance among hypertensive patients.

Despite its universality in human female aging, the menopause and its biology are not completely understood. New biologic mechanisms by which sex hormones may be detrimental or confer protection are continually being discovered. We are now starting to understand that the role of the estrogen receptor is not identical in all tissues. Important nongenomic effects for sex hormones have also been described. Hormone replacement therapy (HRT) has produced effects on health risks: some are reduced, some are increased, and the rest remain uncertain. HRT is being used by an increasing number of women to alleviate climacteric symptoms in the perimenopausal period and to prevent osteoporosis and cardiovascular disease later. Positive effects on Alzheimer's disease and dementia on the one hand, and an increase in venous thrombosis on the other, are currently being reported by several groups. Both the preventive benefits and the risk of breast cancer seem to be linked to long-term and current use. HRT requires further testing through specific clinical trials, currently underway in the United States, before confident recommendations may be made about the full range of benefits and risks.

Even a brief scan of the table of contents of the present volume is enough to disclose the diversity of research interests and opinions in the field of lipidology. It is precisely this diversity that is the strength of our field and that was showcased by the XII International Symposium of DRUGS AFFECTING LIPID METABOLISM (DALM). The papers published here from these proceedings may be divided into three categories: those that define-and refine---our understanding ofthe clinical benefit of aggressive lipid management, those that develop our knowledge of ris!. assessment, and those that discuss the genetic, bio~hemical, and biophysical mechanisms underlying the pathology of coronary heart disease. On the clinical front, further analysis of the results of the Scandinavian Simvastatin Survival Study (4S) has indicated the cost-effectiveness of therapy in patients with established coronary heart disease. The West of Scotland Coronary Prevention Study (WOSCOPS), whose methodology was described at the DALM XII symposium, has demonstrated in a mostly primary-prevention population what 4S demonstrated for secondary prevention the year before: aggressive lipid-regulating therapy reduces coronary heart disease morbidity and mortality rates without concurrently increasing mortality from noncardiovascular causes. In the future, important considerations will be to develop protocols that maximize benefit in groups underrepresented in traditional clinical research­ for example, women and the elderly-and to improve compliance to existing treatment regimens. Furthermore, antioxidant, omega-3 fatty acid, and gene therapies warrant further investigation.